Diabetes mellitus is one of the most common chronic diseases of both the pediatric and adult populations in the U.S. Reduction in pancreatic beta-cell mass is an important causative factor in the pathogenesis of both type 1 and type 2 diabetes. The proposed studies seek to answer basic questions as to how pancreatic beta- cell mass is determined in healthy individuals and in the setting of intrauterine growth retardation (IUGR)- related diabetes. Our hypothesis is that the neonatal period represents a critical window of beta-cell growth and development that determines adult beta-cell mass. Further, we hypothesize that Pdx-1 plays a central role in the determination of beta-cell mass and in the development of IUGR-related diabetes. To test these hypotheses, we will utilize a rodent model of lUGR-related diabetes and Exendin-4 rescue to identify this critical window of beta-cell development. IUGR will also be induced in Pdx-1 overexpressing and haploinsufficient mice to evaluate the role of Pdx-1 in the development of lUGR-related diabetes. In addition, we will utilize a lineage tracing approach to determine the neonatal cellular origins of adult beta-cells in both the normal and IUGR settings.